(1) Background: In the last two decades, anticancer treatment has been extensively developed based on various physical methods, including electroporation (EP). On the basis of many in vitro and in vivo studies, electroporation and further electrochemotherapy (ECT) have been established as a treatment method for cutaneous and subcutaneous lesions. In this procedure, after placing electrodes in the tumor mass and the generation of electrical pulses, a reversible or irreversible rearrangement of the cell membrane occurs. Calcium electroporation has already been applied to treat skin tumors and subcutaneous tissue tumors. Here, we demonstrate the first application of irreversible electroporation (IRE) in combination with calcium ions and chemotherapy for patients with cancer. (2) Methods: This study aimed to present and compare the findings and outcomes of patients with locally advanced pancreatic adenocarcinoma who were qualified for the procedure. Two patients were treated with IRE with calcium ions after chemotherapy (paclitaxel + Gemcitabine (GCB) or FOLOX) or only FOLFOX (folinic acid calcium folinate, fluorouracil, and oxaliplatin). The clinicopathological data, overall survival, and the safety of the procedure were analyzed. (3) Results: Two patients were treated with calcium electroporation. One of the patients developed pancreatitis and the second developed pancreatic fistula, but both of them continued standard systemic treatment. Overall survival was 9 months in the first case and 21 months in the second case (and the patient is still alive). Calcium electroporation had a good impact on QOL (Quality of Life). (4) Conclusions: IRE accompanied chemotherapy, and intratumoral calcium ions administration might represent an additional therapy to surgery and chemotherapy in patients with locally advanced pancreatic cancer (LAPC), particularly in unresectable cases. However, further studies of randomized trials should be undertaken to elucidate the role of chemotherapy in IRE protocols.